编者按：为了体现会议的国际性和多样性，本届胃癌大会设有双语论坛。在中英肿瘤论坛上，来自卡迪夫大学卡迪夫中医研究协作组的Tracey A. Martin教授发表了题为《肝细胞生长因子在脑内皮细胞紧密连接表达及肿瘤转移的影响》的报告。在中德肿瘤论坛上， 德国拜罗伊特医学中心Michael Vieth 的教授作了《胃组织学中的有趣发现》的报告，现将内容整理如下

肝细胞生长因子在脑内皮细胞紧密连接表达及肿瘤转移的影响

Tracey A. Martin    卡迪夫大学卡迪夫中医研究协作组

　　大脑的血管覆盖排列着紧密相嵌在一起的内皮细胞，在大脑组织及血流中间创造了一个几乎无法渗透的分界线。血脑屏障可以保护神经组织免受血液成分及毒素的变化导致的破坏。构成血脑屏障的内皮细胞可以非常专业地对进入或离开大脑的物质进行精准的调控。

　　脑转移是颅内肿瘤中十分重要的组成部分。在美国，每年大约诊断17万的转移性脑肿瘤，而每年有1万7千例新诊断的原发性脑肿瘤。脑转移的大部分来源于肺癌（40%~50%），乳腺癌（15%~25%）以及恶性黑色素瘤（5%~20%）。在这些肿瘤当中，黑色素瘤是最常转移至大脑的肿瘤：有40%~50%的病例被诊断有脑转移，而在尸检后会另外增加30~40%的脑转移病例。脑转移提示患者的预后很差，5年生存率低于10%。

　　紧密连接（TJ）是相邻细胞的细胞膜组成的一系列联系，这种联系看起来将细胞外的空间完全封闭，从而创造一个细胞内屏障及膜内扩散的“栅栏”。在上皮细胞中，紧密连接起着粘合剂的作用，可以防止细胞分解，然而在内皮细胞中，紧密连接起到屏障的作用，小分子和炎症细胞可以通过。在过去的二十年，生物医学已经发现了与紧密连接相关的超过70种的“新”疾病。

　　紧密连接在肿瘤转移中被认为是关键性角色。早期研究显示紧密连接蛋白表达的下降与肿瘤分化之间存在联系，已出现越来越多的实验证据证实紧密连接是一个作为前线的结构，是肿瘤细胞转移过程中必须要克服的。

　　目前治疗恶性肿瘤脑转移的方法有限，因此防止出现脑转移至关重要。可能的方法之一是将通过血脑屏障的转移性细胞的转移过程作为靶点。这个过程的机制大部分并不典型，然而除去防止肿瘤细胞进入大脑外，大脑内皮细胞似乎也在转移性细胞外渗过程中起到保护作用。了解这些机制对于我们找到防止脑转移形成的靶点是十分必要的。

　　肝细胞生长因子（HGF）是由间叶细胞/基质细胞分泌的强有力的细胞生长、运动及形态生成因子。它介导细胞的侵袭性生长和上皮间质转化，并通过酪氨酸激酶c-met受体以上皮细胞或内皮细胞作为靶标。HGF/Met的异常激活参与了肿瘤的扩散。

　　紧密连接分子的表达模式在不同器官的内皮细胞中有所不同。另外，它们在功能上也有所不同，这与屏障的功能相关。这与肿瘤细胞通过血脑屏障转移的能力有着直接的关联，关于如何控制转移也因此而提出很多问题。我们发现永生化大脑内皮细胞在培养基中生长良好，它被应用于描述如何通过间叶细胞生成因子HGF来调节紧密连接。HGF对脑转移有着双重作用。除增加肿瘤细胞转移及侵袭能力之外，我们的结果显示HGF对脑内皮细胞同样有着直接作用，它可以增加细胞运动并重新组织紧密连接的蛋白分布。HGF潜在地削弱由脑内皮细胞生成的专门的渗透屏障，从而导致肿瘤的脑转移。为了以一种与生物学更加相关的方式来研究它们，进一步的研究工作会阐述如何加速这种调控，以及为了增加体外这些细胞紧密连接的作用，我们应该用何治疗手段。

　　The brain’s blood vessels are lined with endothelial cells that are wedged tightly together， creating a nearly impermeable boundary between the brain and bloodstream. The blood-brain barrier (BBB) protects the neural tissue from variations in blood composition and toxins. The endothelial cells forming the blood-brain barrier are highly specialized to allow precise control over the substances that enter or leave the brain.

　　Brain metastases constitute a significant part of intracranial tumours. In the United States， about 170，000 metastatic brain tumours are diagnosed annually whereas primary tumours represent 17，000 new cases/year. The majority of brain metastases originate from lung cancer (40%–50%)， breast cancer (15%–25%) and malignant melanoma (5%–20%).

　　The TJ is a region where the plasma membrane of adjacent cells forms a series of contacts that appear to completely occlude the extracellular space thus creating an intercellular barrier and intramembrane diffusion fence.

　　Tight Junctions have become recognised as key players in cancer metastasis. Early studies suggested a link between the reduction of tight junction proteins and tumour differentiation and increasing experimental evidence has emerged to place tight junctions in the frontline as the structure that cancer cells must overcome in order to metastasize.

　　Brain metastases of malignant tumours have limited therapeutic options. Hence， it would be of crucial importance to prevent the formation of brain metastases. One of the possible strategies is to target the step of migration of metastatic cells through the blood-brain barrier. Hepatocyte Growth Factor (HGF) is potent cell growth， motility and morphogenic factor， secreted by mesenchymal/stromal cells. It mediates invasive growth and epithelial-mesenchymal transition (EMT) and targets epithelial & endothelial cells via tyrosine kinase c-met receptor. Aberrant activation HGF/MET involved in cancer spread.

　　We have now identified several proteins that we anticipate may be of importance to the passage of cancer cells through the blood brain barrier. The expression pattern of TJ molecules varies widely between endothelial cells of different origins. Moreover， they also differ functionally， which is particularly pertinent to barrier function. Further work will elucidate how this control can be expedited and which treatments can be used in order to enhance the TJ function of these cells invitro， in order to study them in a more biologically relevant way.

胃组织学中的有趣发现

Michael Vieth    德国拜罗伊特医学中心

　　幽门螺杆菌感染在人类当中是一种长期存在的感染，它被世界卫生组织WHO认为是I类致癌物。幸运的是，仅有一小部分的感染人群会出现严重的感染后遗症，如胃溃疡、癌症和淋巴瘤。在工业化国家，胃癌的数量在逐渐减少。这个趋势同样被德国拜罗伊特医学中心综合癌症中心的病理科所发现。他们发现所谓的胃癌发生的多步骤假说（萎缩性胃炎向癌转变的级联反应），即Correa假说是一个理想化的模型，它并不存在于所有个体当中。所谓的以胃体为主的胃炎人群胃癌的发生风险最高，通常，发生在上半部分胃的胃炎相比于发生在下半部分胃（胃窦）更为严重。

　　一旦被诊断为癌前病变，如不典型增生或上皮内瘤样变，需要注意的是要有可以对病变进行分级和分类继而能对转变为恶性病变的风险进行评定的组织学标准。不幸的是，这些标准并未在全球范围内得到公认。这会导致在世界的某些地方，同样的病变被诊断为不典型增生而在其它地方被诊断为侵袭性肿瘤。因此在世界范围内统一这些术语是十分必要的。

　　肿瘤性改变的鉴别诊断包括药物导致的病变。如果所谓的胃炎情况已知，那么病理学家会更加肯定诊断（不存在幽门螺杆菌感染的胃癌被认为是不寻常的，需要进一步提出质疑，并同严重的反应性损伤进行鉴别）。标准的胃部活检包括胃窦2处和胃体2处。由于胃的大部分病变是肿瘤样病变，合理的程序是首先进行胃部病变的活检，然后在接收到组织学报告后进行进一步治疗。这个过程可以保证高质量的胃组织学报告，及胃部炎症改变的病因学的发现。

　　Helicobacter infection is a long standing infection in mankind and is considered to represent a class I carcinogen by the WHO. Fortunately， a small subset of all infected individuals will suffer from severe sequele of the infection like gastric ulcerations， carcinoma and lymphoma. In industrialized countries the number of gastric cancer is decreasing. A trend that has also been observed among more than 1.3 million patients within the last 3 decades at the Institute of Pathology at the comprehensive cancer center of the Klinikum Bayreuth. It turned out that the so called gastritis-atrophy-metaplasia-cancer sequence (Correa Hypothesis) is an ideal model that is not necessarly present in all individuals. The highest risk for gastric carcinoma can be found in individuals with so called corpus-dominant gastritis with more severe gastritis in the upper part of the stomach compared to the lower part (antrum).

　　In case precancerous lesions like dysplasia or intraepithelial neoplasia are diagnosed  it needs to be noted that there are histological criteria available that allow to grade and classify lesions and subsequently the risk for malignant transformation. Unfortunately the criteria are not worldwide validated. This leads to the situation that in some parts of the world lesions are classified as dysplasia whereas in other parts of the world such lesions are classified as invasive carcinoma. A worldwide effort to harmonize terminology is needed.

　　The differential diagnosis of neoplastic changes include drug induced lesions. Pathologists can be more sure about a diagnosis if the so called gastritis status is known (e.g. a carcinoma in a stomach with no Helicobacter needs to be regarded rather unusal and should be questioned and differentiated from severe reactive lesions). The standard set of gastric biopsies include 2 antrum and 2 corpus biopsies each. Since most lesions in the stomach are tumour-like lesions it is justified to bisopy gastric lesions frist and take further therapeutic steps after the histological report is received. This procedure ensures high quality of gastric histology with identification of the correct etiology of inflammatory changes in the stomach.